Molecular genetic principles will be used to produce murine analogs of inherited human diseases for which spontaneous mutants are not available. Murine genomic and cDNA clones for murine glucocerebrosidase were isolated, characterized, and mapped to mouse chromosome 3 and introduced into cultured murine embryonic stem cells by electroporation. Methods have been validated using polymerase chain reactions and genomic Southern hybridizations to identify which clones of the 10(8) progenitor cells that were electroporated are carrying an inactivated glucocerebrosidase gene. Functional analysis of the promoter region of the murine glucocerebrosidase gene has been performed in order to discover positive regulators of glucocerebrosidase gene expression. Discovery and administration of these positive regulators to humans could allow augmentation of the low residual level of glucocerebrosidase activity in patients with Gaucher's disease.